The fact that psychologic stress can precipitate or alter the course of organic diseases has long been recognized. An essential challenge in psychosomatic-psychobiological research is to delineate the mechanisms by which experience causes certain types of physiological reactions that result in disease states. In addition, the mechanisms of neurobiological modulating systems need to be understood at the molecular and genetic levels. Recent and ongoing developments in cellular and molecular biology provide some research models by which transducing mechanisms involved in psychosomatic reactions can be understood at the most fundamental level. It has been suggested that anxiety can occur as a result of acquired neurophysiological chemosensitivity. Stimuli that produce xe2x80x9cchronic anxietyxe2x80x9d in the sea snail aplysia cause the enhancement of connections made by the sensory neurons on their target cellsxe2x80x94that is, interneurons and motor neurons. The enhancing process, deemed postsynaptic facilitation, is caused by noxious stimuli that activate cells that use a serotonin-like neurotransmitter. Those cells on the head of the aplysia act as a defensive arousal system, impinge on the synaptic terminals of the reflex system for gill withdrawal, and enhance the connections that the sensory synapses make on the motor neurons and interneurons. Serotonin appears to play a major role in the defensive arousal process by increasing intracellular cAMP, which then strengthens the neuroconnectors of the sensory neurons by facilitating neurotransmitter release. In accordance with the present invention, substance P has been found to play an important role in the inducement of disease states by psychobiological reactions.
With respect to psychoimmunologic disorders, interest in the interactions between the central nervous system and the immune system date back to Aristotle, who hypothesized a connection between physical health and mood. Later, Sir William Osler spoke of the importance of knowing what is going on in a patient""s head, as well as the lungs, in predicting the outcome of pulmonary tuberculosis. During the mid 1950s Selye demonstrated a clear relation among brain activity, endocrine organs, and immune function. In 1964 the field was first referred to as psychoimmunology, later amended to psychoneuroimmunology, the study of the interaction of consciousness, the brain and the central nervous system, and the body""s immune system. In recent years major advances have been made in establishing direct evidence for a brain-immune system relation. In serving functions of adaptation and defense, both the central nervous system and the immune system discriminate between self and nonself, and they incorporate principles of recognition, learning, memory, and transmission of information. Evidence for such a communication system ranges from anatomical confirmation of the central nervous system innervation of immune organs to reports documenting the behavioral effects on immune response and tumor acquisition in experimental animals. A number of studies involving experimental animals and human autopsy specimens have shown direct sympathetic nervous system innervation of the spleen, the thymus, and the lymph nodes. Cholinergic innervation of the thymus gland has now been documented, and investigators have described noradrenergic innervation of lymphoid tissue in a variety of mammalian species, including humans.
Lending further evidence is the presence of receptors for various neurotransmitters, neurohormones, and neuropeptides on cells of the immune system. In particular, neurokinin receptors have been found in lymphatic tissue. Noradrenergic receptors have been found on lymphocytes that appear to be exclusively for beta2-adrenergic receptors, which are similar to those found in the smooth muscles of the bronchi and the lungs. In addition to the noradrenergic receptors of the beta-1 subtype, evidence indicates the presence on lymphocytes of receptors for gonadal steroids, endorphins, enkephalins, corticotropin, vasointestinal peptide, cholecystokinin, neurotensin, acetylcholine, and serotonin. Recent evidence also indicates that lymphocytes may synthesize some neurohormones de novo.
Although some studies suggest that bereavement and depression can interfere with immunological competence, the findings in this area of research have been diverse and often inconsistent. Studies of bereaved men and women have reported reduced in vitro lymphocyte response to mitogen stimulation, with normal levels of circulating immunoglobulins and normal responses on delayed hypersensitivity skin tests; the reduced lymphocyte response is most dramatic in bereaved patients with depressive symptoms. A recent meta-analysis of methodologically sound studies addressing cellular immunity in depression found that the immune abnormalities reliably associated with depression were (1) decreased proliferative response of lymphocytes to mitogen stimulation, (2) decreased natural killer cell activity, and (3) abnormalities of different white blood cell lines. The magnitude of these immune system abnormalities correlated with the intensity of depressed mood. However, methodological concerns limit the interpretation and generalizability of much of the available data on the immune system in depression; there is a high incidence of failure to replicate findings.
Although the present invention is not limited to a specific mechanism of action, the inventors postulate that a potential explanation for some of the diverse findings may involve high catecholamine output and the increased production of prostaglandins, each of which has been observed separately in studies of depressed patients. Catecholamines, acting through beta-adrenergic receptors, are known to suppress the activity of human natural killer cells. Prostaglandins, functioning through a complex interaction between second messenger systems, may inhibit in vitro mitogen-induced lymphocyte proliferation. Because recent animal work suggests that prostaglandin production is increased by catecholamines through a nonreceptor-mediated mechanism, the diminished immunological competence reported in depressed patients may be a result of the dysregulation of the catecholaminergic system. In accordance with the present invention, the neuropeptide substance P is postulated to play in important role in this mechanism. Accordingly, a tacykinin antagonist, in particular a neurokinin-1 receptor antagonist would be useful in the treatment or prevention of a psychosomatic disorder or a psychoimmunologic disorder.
Antidepressant and antianxiety agents have been employed for psychosomatic or psychoimmunologic disorders with limited success. In addition, certain side effects may be present with such treatment. These approaches have had limited success, however, and an alternate means of treating or preventing psychosomatic or psychoimmunologic disorders would be of great benefit.
The neuropeptide receptors for substance P (neurokinin-1; NK-1) are widely distributed throughout the mammalian nervous system (especially brain and spinal ganglia), the circulatory system and peripheral tissues (especially the duodenum and jejunum) and are involved in regulating a number of diverse biological processes. This includes sensory perception of olfaction, vision, audition and pain, movement control, gastric motility, vasodilation, salivation, and micturition (B. Pernow, Pharmacol. Rev., 1983, 35, 85-141). The NK-1 and NK-2 receptor subtypes are implicated in synaptic transmission (Laneuville et al., Life Sci., 42, 1295-1305 (1988)).
Substance P is a naturally occurring undecapeptide belonging to the tachykinin family of peptides, the latter being so-named because of their prompt contractile action on extravascular smooth muscle tissue. The tachykinins are distinguished by a conserved carboxyl-terminal sequence. In addition to SP the known mammalian tachykinins include neurokinin A and neurokinin B. The current nomenclature designates the receptors for substance P, neurokinin A, and neurokinin B as neurokinin-1, neurokinin-2, and neurokinin-3, respectively.
Substance P is a pharmacologically-active neuropeptide that is produced in mammals and acts as a vasodilator, a depressant, stimulates salivation and produces increased capillary permeability. It is also capable of producing both analgesia and hyperalgesia in animals, depending on dose and pain responsiveness of the animal (see R. C. A. Frederickson et al., Science 199, 1359 (1978); P. Oehme et al. Science, 208, 305 (1980)) and plays a role in sensory transmission and pain perception (T. M. Jessell, Advan. Biochem. Psvchopharmacol. 28, 189 (1981)).
Neurokinin-1 (NK-1; substance P) receptor antagonists are being developed for the treatment of a number of physiological disorders associated with an excess or imbalance of tachykinins, and in particular substance P. Examples of conditions in which substance P has been implicated include disorders of the central nervous system such as anxiety, depression and psychosis (see, for instance, PCT Patent Publication Nos. WO 95/16679, WO 95/18124 and WO 95/23798). More recently, PCT Patent Publication No WO 96/24353 suggests that a more efficacious and safe treatment of psychiatric disorders would be achieved using a combination of a tachykinin antagonist and a serotonin agonist or selective serotonin reuptake inhibitor (SSRI). However, such as regimen would not be free of side-effects due to the serotonin agonist or SSRI. Currently there are only limited means for treating or preventing psychosomatic or psychoimmunologic disorders. In view of the short-comings of existing agents, there is a need for new effective methods for treating or preventing psychosomatic and psychoimmunologic disorders.
The present invention relates to the use of a tachykinin receptor antagonist, in particular a neurokinin-1 receptor antagonist, for the treatment or prevention of a psychosomatic disorder or a psychoimmunologic disorder or the amelioration of symptoms attendant to a psychosomatic disorder or a psychoimmunologic disorder comprising the administration of a tachykinin antagonist, in particular a neurokinin-1 receptor antagonist. In a preferred embodiment, the present invention provides a method for treatment or prevention of a psychosomatic disorder or a psychoimmunologic disorder or the amelioration of symptoms attendant to a psychosomatic disorder or a psychoimmunologic disorder comprising the administration of a tachykinin receptor antagonist, in particular a neurokinin-1 receptor antagonist.
The present invention is directed to a method for treating or preventing a psychosomatic disorder in a patient comprising the administration of a tachykinin receptor antagonist, in particular an NK-1 receptor antagonist.
The present invention is further directed to a method for treating or preventing a psychoimmunologic disorder in a patient comprising the administration of a tachykinin receptor antagonist, in particular an NK-1 receptor antagonist.
The present invention is further directed to a method for ameliorating the symptoms attendant to a psychosomatic disorder or a psychoimmunologic disorder in a patient comprising the administration of a tachykinin receptor antagonist, in particular an NK-1 receptor antagonist.
In a preferred embodiment, the present invention provides a method for treating or preventing a psychosomatic disorder in a patient comprising the administration of a tachykinin receptor antagonist, in particular an NK-1 receptor antagonist. In a more preferred embodiment, the present invention provides a method for diminishing or severing the detrimental influence of psychological stimuli in a disease or disorder for which the physical etiology is contributed to directly or indirectly by psychological factors.
In a preferred embodiment, the present invention provides a method for treating or preventing a psychoimmunologic disorder in a patient comprising the administration of a tachykinin receptor antagonist, in particular an NK-1 receptor antagonist. In a more preferred embodiment, the present invention provides a method for diminishing or severing the direct or indirect detrimental influence of psychological stimuli on the immunological state of a patient by employing an NK-1 receptor antagonist.
In a preferred embodiment, the present invention further provides a method for ameliorating the symptoms attendant to a psychosomatic disorder or a psychoimmunologic disorder in a patient comprising the administration of a tachykinin receptor antagonist, in particular an NK-1 receptor antagonist.
The present invention further provides a pharmaceutical composition for treating or preventing a psychosomatic disorder or a psychoimmunologic disorder in a patient comprising a tachykinin receptor antagonist, in particular an NK-1 receptor antagonist, together with at least one pharmaceutically acceptable carrier or excipient.
The present invention further provides a pharmaceutical composition for ameliorating the symptoms attendant to a psychosomatic disorder or a psychoimmunologic disorder in a patient comprising a tachykinin receptor antagonist, in particular an NK-1 receptor antagonist, together with at least one pharmaceutically acceptable carrier or excipient.
In accordance with the present invention the tachykinin receptor antagonist is administered to a patient in a quantity sufficient to treat or prevent the symptoms and/or underlying etiology associated with the psychosomatic or psychoimmunologic disorder in a patient.
In a further aspect of the present invention, there is provided a pharmaceutical composition for treating or preventing a psychosomatic disorder or a psychoimmunologic disorder in a patient comprising a NK-1 receptor antagonist, together with at least one pharmaceutically acceptable carrier or excipient.
In a further aspect of the present invention, there is provided a pharmaceutical composition ameliorating the symptoms attendant to a psychosomatic disorder or a psychoimmunologic disorder in a patient comprising a NK-1 receptor antagonist, together with at least one pharmaceutically acceptable carrier or excipient.
The present invention also provides the use of a NK-1 receptor antagonist for the manufacture of a medicament for treating or preventing a psychosomatic disorder or a psychoimmunologic disorder in a patient.
The present invention also provides the use of a NK-1 receptor antagonist for the manufacture of a medicament for ameliorating the symptoms attendant to a psychosomatic disorder or a psychoimmunologic disorder in a patient.
It is well recognized in the art that psychological stimuli can precipitate or alter the course of numerous diseases or disorders. As used herein a xe2x80x9cpsychosomatic disorderxe2x80x9d is a disease or disorder for which the physical etiology is contributed to directly or indirectly by psychological factors. As used herein a xe2x80x9cpsychoimmunologic disorderxe2x80x9d is an immunologic disease or disorder wherein an immunological response is influenced directly or indirectly by psychological factors.
Although the present invention is useful in any mammal suffering from psychosomatic disorder or a psychoimmunologic disorders, a preferred subject is a human.
The tachykinin receptor antagonists of use in the present invention may be any tachykinin antagonist known from the art. Preferably, the tachykinin receptor antagonist is a neurokinin-1 (NK-1) or neurokinin-2 (NK-2) receptor antagonist, especially a neurokinin-1 (NK-1) receptor antagonist.
The tachykinin antagonist may be peptidal or non-peptidal in nature, however, the use of a non-peptidal tachykinin receptor antagonist is preferred. In addition, for convenience the use of an orally active tachykinin receptor antagonist is preferred.
In the present invention, it is preferred that the tachykinin receptor antagonist is active upon the central nervous system (CNS), such as the brain, following systemic administration, i.e. that it readily penetrates the CNS. Accordingly, a preferred tachykinin antagonist for use in the present invention is a CNS-penetrating tachykinin antagonist, especially a CNS-penetrating NK-1 antagonist. An especially preferred class of NK-1 receptor antagonist of use in the present invention are those compounds which are orally active, long acting and CNS-penetrant.
Neurokinin-1 receptor antagonists of use in the present invention are fully described, for example, in U.S. Pat. Nos. 5,162,339, 5,232,929, 5,242,930, 5,373,003, 5,387,595, 5,459,270, 5,494,926, 5,496,833, 5,637,699; European Patent Publication Nos. EP 0 360 390, 0 394 989, 0 428 434, 0 429 366, 0 430 771, 0 436 334, 0 443 132, 0 482 539, 0 498 069, 0 499 313, 0 512 901, 0 512 902, 0 514 273, 0 514 274, 0 514 275, 0 514 276, 0 515 681, 0 517 589, 0 520 555, 0 522 808, 0 528 495, 0 532 456, 0 533 280, 0 536 817, 0 545 478, 0 558 156, 0 577 394, 0 585 913,0 590 152, 0 599 538, 0 610 793, 0 634 402, 0 686 629, 0 693 489, 0 694 535, 0 699 655, 0 699 674, 0 707 006, 0 708 101, 0 709 375, 0 709 376, 0 714 891, 0 723 959, 0 733 632 and 0 776 893; PCT International Patent Publication Nos. WO 90/05525, 90/05729, 91/09844, 91/18899, 92/01688, 92/06079, 92/12151, 92/15585, 92/17449, 92/20661, 92/20676, 92/21677, 92/22569, 93/00330, 93/00331, 93/01159, 93/01165, 93/01169, 93/01170, 93/06099, 93/09116, 93/10073, 93/14084, 93/14113, 93/18023, 93/19064, 93/21155, 93/21181, 93/23380, 93/24465, 94/00440, 94/01402, 94/02461, 94/02595, 94/03429, 94/03445, 94/04494, 94/04496, 94/05625, 94/07843, 94/08997, 94/10165, 94/10167, 94/10168, 94/10170, 94/11368, 94/13639, 94/13663, 94/14767, 94/15903, 94/19320, 94/19323, 94/20500, 94/26735, 94/26740, 94/29309, 95/02595, 95/04040, 95/04042, 95/06645, 95/07886, 95/07908, 95/08549, 95/11880, 95/14017, 95/15311, 95/16679, 95/17382, 95/18124, 95/18129, 95/19344, 95/20575, 95/21819, 95/22525, 95/23798, 95/26338, 95/28418, 95/30674, 95/30687, 95/33744, 96/05181, 96/05193, 96/05203, 96/06094, 96/07649, 96/10562, 96/16939, 96/18643, 96/20197, 96/21661, 96/29304, 96/29317, 96/29326, 96/29328, 96/31214, 96/32385, 96/37489, 97/01553, 97/01554, 97/03066, 97/08144, 97/14671, 97/17362, 97/18206, 97/19084, 97/19942 and 97/21702; and in British Patent Publication Nos. 2 266 529, 2 268 931, 2 269 170, 2 269 590, 2 271 774, 2 292 144, 2 293 168, 2 293 169, and 2 302 689. The preparation of such compounds is fully described in the aforementioned patents and publications.
Particularly preferred NK-1 receptor antagonists are those described in PCT International Patent Publication No. WO 95/16679 and European Patent Publication No. 0 577 394 as compounds of formula (I): 
or a pharmaceutically acceptable salt thereof, wherein:
R1 is selected from the group consisting of:
(1) hydrogen;
(2) C1-6 alkyl, unsubstituted or substituted with one or more of the substituents selected from:
(a) hydroxy,
(b) oxo,
(c) C1-6 alkoxy,
(d) phenyl-C1-3 alkoxy,
(e) phenyl,
(f) xe2x80x94CN,
(g) halo, wherein halo is fluoro, chloro, bromo or iodo,
(h) xe2x80x94NR9R10, wherein R9 and R10 are independently selected from:
(i) hydrogen,
(ii) C1-6 alkyl,
(iii) hydroxy-C1-6 alkyl, and
(iv) phenyl,
(i) xe2x80x94NR9COR10,
(j) xe2x80x94NR9CO2R10,
(k) xe2x80x94CONR9R10,
(l) xe2x80x94COR9,
(m) xe2x80x94CO2R9,
(n) heterocycle, wherein the heterocycle is selected from the group consisting of:
(A) benzimidazolyl,
(B) benzofuranyl,
(C) benzothiophenyl,
(D) benzoxazolyl,
(E) furanyl,
(F) imidazolyl,
(G) indolyl,
(H) isooxazolyl,
(I) isothiazolyl,
(J) oxadiazolyl,
(K) oxazolyl,
(L) pyrazinyl,
(M) pyrazolyl,
(N) pyridyl,
(O) pyrimidyl,
(P) pyrrolyl,
(Q) quinolyl,
(R) tetrazolyl,
(S) thiadiazolyl,
(T) thiazolyl,
(U) thienyl,
(V) triazolyl,
(W) azetidinyl,
(X) 1,4-dioxanyl,
(Y) hexahydroazepinyl,
(Z) piperazinyl,
(AA) piperidinyl,
(AB) pyrrolidinyl,
(AC) tetrahydrofuranyl, and
(AD) tetrahydrothienyl,
and wherein the heterocycle is unsubstituted or substituted with one or more substituent(s) selected from:
(i) C1-6 alkyl, unsubstituted or substituted with halo, xe2x80x94CF3, xe2x80x94OCH3, or phenyl,
(ii) C1-6 alkoxy,
(iii) oxo,
(iv) hydroxy,
(v) thioxo,
(vi) xe2x80x94SR9,
(vii) halo,
(viii) cyano,
(ix) phenyl,
(x) trifluoromethyl,
(xi) xe2x80x94(CH2)mxe2x80x94NR9R10, wherein m is 0, 1 or 2,
(xii) xe2x80x94NR9COR10,
(xiii) xe2x80x94CONR9R10,
(xiv) xe2x80x94CO2R9, and
(xv) xe2x80x94(CH2)mxe2x80x94OR9;
(3) C2-6 alkenyl, unsubstituted or substituted with one or more of the substituent(s) selected from:
(a) hydroxy,
(b) oxo,
(c) C1-6alkoxy,
(d) phenyl-C1-3 alkoxy,
(e) phenyl,
(f) xe2x80x94CN,
(g) halo,
(h) xe2x80x94CONR9R10,
(i) xe2x80x94COR9,
(j) xe2x80x94CO2R9,
(k) heterocycle;
(4) C2-6 alkynyl;
(5) phenyl, unsubstituted or substituted with one or more of the substituent(s) selected from:
(a) hydroxy,
(b) C1-6 alkoxy,
(c) C1-6 alkyl,
(d) C2-5 alkenyl,
(e) halo,
(f) xe2x80x94CN,
(g) xe2x80x94NO2,
(h) xe2x80x94CF3,
(i) xe2x80x94(CH2)mxe2x80x94NR9R10,
(j) xe2x80x94NR9COR10,
(k) xe2x80x94NR9CO2R10,
(l) xe2x80x94CONR9R10,
(m) xe2x80x94CO2NR9R10,
(n) xe2x80x94COR9,
(o) xe2x80x94CO2R9;
R2 and R3 are independently selected from the group consisting of:
(1) hydrogen,
(2) C1-6 alkyl, unsubstituted or substituted with one or more of the substituents selected from:
(a) hydroxy,
(b) oxo,
(c) C1-6 alkoxy,
(d) phenyl-C1-3 alkoxy,
(e) phenyl,
(f) xe2x80x94CN,
(g) halo,
(h) xe2x80x94NR9R10,
(i) xe2x80x94NR9COR10,
(j) xe2x80x94NR9CO2R10,
(k) xe2x80x94CONR9R10,
(l) xe2x80x94COR9, and
(m) xe2x80x94CO2R9;
(3) C2-6 alkenyl, unsubstituted or substituted with one or more of the substituent(s) selected from:
(a) hydroxy,
(b) oxo,
(c) C1-6 alkoxy,
(d) phenyl-C1-3 alkoxy,
(e) phenyl,
(f) xe2x80x94CN,
(g) halo,
(h) xe2x80x94CONR9R10,
(i) xe2x80x94COR9, and
(j) xe2x80x94CO2R9;
(4) C2-6 alkynyl;
(5) phenyl, unsubstituted or substituted with one or more of the substituent(s) selected from:
(a) hydroxy,
(b) C1-6 alkoxy,
(c) C1-6 alkyl,
(d) C2-5 alkenyl,
(e) halo,
(f) xe2x80x94CN,
(g) xe2x80x94NO2,
(h) xe2x80x94CF3,
(i) xe2x80x94(CH2)mxe2x80x94NR9R10,
(j) xe2x80x94NR9COR10,
(k) xe2x80x94NR9CO2R10,
(l) xe2x80x94CONR9R10,
(m) xe2x80x94CO2NR9R10,
(n) xe2x80x94COR9, and
(o) xe2x80x94CO2R9;
and the groups R1 and R2 may be joined together to form a heterocyclic ring selected from the group consisting of:
(a) pyrrolidinyl,
(b) piperidinyl,
(c) pyrrolyl,
(d) pyridinyl,
(e) imidazolyl,
(f) oxazolyl, and
(g) thiazolyl,
and wherein the heterocyclic ring is unsubstituted or substituted with one or more substituent(s) selected from:
(i) C1-6alkyl,
(ii) oxo,
(iii) C1-6alkoxy,
(iv) xe2x80x94NR9R10,
(v) halo, and
(vi) trifluoromethyl;
and the groups R2 and R3 may be joined together to form a carbocyclic ring selected from the group consisting of:
(a) cyclopentyl,
(b) cyclohexyl,
(c) phenyl,
and wherein the carbocyclic ring is unsubstituted or substituted with one or more substituents selected from:
(i) C1-6alkyl,
(ii) C1-6alkoxy,
(iii) xe2x80x94NR9R10,
(iv) halo, and
(v) trifluoromethyl;
and the groups R2 and R3 may be joined together to form a heterocyclic ring selected from the group consisting of:
(a) pyrrolidinyl,
(b) piperidinyl,
(c) pyrrolyl,
(d) pyridinyl,
(e) imidazolyl,
(f) furanyl,
(g) oxazolyl,
(h) thienyl, and
(i) thiazolyl,
and wherein the heterocyclic ring is unsubstituted or substituted with one or more substituent(s) selected from:
(i) C1-6alkyl,
(ii) oxo,
(iii) C1-6alkoxy,
(iv) xe2x80x94NR9R10,
(v) halo, and
(vi) trifluoromethyl;
R6, R7 and R8 are independently selected from the group consisting of:
(1) hydrogen;
(2) C1-6 alkyl, unsubstituted or substituted with one or more of the substituents selected from:
(a) hydroxy,
(b) oxo,
(c) C1-6 alkoxy,
(d) phenyl-C1-3 alkoxy,
(e) phenyl,
(f) xe2x80x94CN,
(g) halo,
(h) xe2x80x94NR9R10,
(i) xe2x80x94NR9COR10,
(j) xe2x80x94NR9CO2R10,
(k) xe2x80x94CONR9R10,
(l) xe2x80x94COR9, and
(m) xe2x80x94CO2R9;
(3) C2-6 alkenyl, unsubstituted or substituted with one or more of the substituent(s) selected from:
(a) hydroxy,
(b) oxo,
(c) C1-6 alkoxy,
(d) phenyl-C1-3 alkoxy,
(e) phenyl,
(f) xe2x80x94CN,
(g) halo,
(h) xe2x80x94CONR9R10,
(i) xe2x80x94COR9, and
(j) xe2x80x94CO2R9;
(4) C2-6 alkynyl;
(5) phenyl, unsubstituted or substituted with one or more of the substituent(s) selected from:
(a) hydroxy,
(b) C1-6 alkoxy,
(c) C1-6 alkyl,
(d) C2-5 alkenyl,
(e) halo,
(f) xe2x80x94CN,
(g) xe2x80x94NO2,
(h) xe2x80x94CF3,
(i) xe2x80x94(CH2)mxe2x80x94NR9R10,
(j) xe2x80x94NR9COR10,
(k) xe2x80x94NR9CO2R10,
(l) xe2x80x94CONR9R10,
(m) xe2x80x94CO2NR9R10,
(n) xe2x80x94COR9,
(o) xe2x80x94CO2R9;
(6) halo,
(7) xe2x80x94CN,
(8) xe2x80x94CF3,
(9) xe2x80x94NO2,
(10) xe2x80x94SR14, wherein R14 is hydrogen or C1-5alkyl,
(11) xe2x80x94SOR14,
(12) xe2x80x94SO2R14,
(13) NR9COR10,
(14) CONR9COR10,
(15) NR9R10,
(16) NR9CO2R10,
(17) hydroxy,
(18) C1-6alkoxy,
(19) COR9,
(20) CO2R9,
(21) 2-pyridyl,
(22) 3-pyridyl,
(23) 4-pyridyl,
(24) 5-tetrazolyl,
(25) 2-oxazolyl, and
(26) 2-thiazolyl;
R11, R12 and R13 are independently selected from the definitions of R6, R7 and R8;
X is selected from the group consisting of:
(1) xe2x80x94Oxe2x80x94,
(2) xe2x80x94Sxe2x80x94,
(3) xe2x80x94SOxe2x80x94, and
(4) xe2x80x94SO2xe2x80x94;
Y is selected from the group consisting of:
(1) a single bond,
(2) xe2x80x94Oxe2x80x94,
(3) xe2x80x94Sxe2x80x94,
(4) xe2x80x94COxe2x80x94,
(5) xe2x80x94CH2xe2x80x94,
(6) xe2x80x94CHR15xe2x80x94, and
(7) xe2x80x94CR15R16xe2x80x94, wherein R15 and R16 are independently selected from the group consisting of:
(a) C1-6 alkyl, unsubstituted or substituted with one or more of the substituents selected from:
(i) hydroxy,
(ii) oxo,
(iii) C1-6 alkoxy,
(iv) phenyl-C1-3 alkoxy,
(v) phenyl,
(vi) xe2x80x94CN,
(vii) halo,
(viii) xe2x80x94NR9R10,
(ix) xe2x80x94NR9COR10,
(x) xe2x80x94NR9CO2R10,
(xi) xe2x80x94CONR9R10,
(xii) xe2x80x94COR9, and
(xiii) xe2x80x94CO2R9;
(b) phenyl, unsubstituted or substituted with one or more of the substituent(s) selected from:
(i) hydroxy,
(ii) C1-6 alkoxy,
(iii) C1-6 alkyl,
(iv) C2-5 alkenyl,
(v) halo,
(vi) xe2x80x94CN,
(vii) xe2x80x94NO2,
(viii) xe2x80x94CF3,
(ix) xe2x80x94(CH2)mxe2x80x94NR9R10,
(x) xe2x80x94NR9COR10,
(xi) xe2x80x94NR9CO2R10,
(xii) xe2x80x94CONR9R10,
(xiii) xe2x80x94CO2NR9R10,
(xiv) xe2x80x94COR9, and
(xv) xe2x80x94CO2R9; and
Z is C1-6 alkyl.
Particularly preferred compounds of formula (I) include:
4-(3-(1,2,4-triazolo)methyl)-2(S)-(3,5-bis(trifluoromethyl)benzyloxy)-3(S)-phenyl-morpholine;
4-(3-(1,2,4-triazolo)methyl)-2(S)-(3,5-bis(trifluoromethyl)benzyloxy)-3(R)-phenyl-morpholine;
4-(3-(5-oxo-1H,4H-1,2,4-triazolo)methyl)-2(S)-(3,5-bis(trifluoromethyl)benzyloxy)-3(S)-phenyl-morpholine; and
2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-3-(S)-(4-fluorophenyl)-4-(3-(5-oxo-1H,4H-1,2,4-triazolo)methyl)morpholine; or a pharmaceutically acceptable salt thereof.
An especially preferred compound of formula (I) is
2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyliethoxy)-3-(S)-(4-fluorophenyl)-4-(3-(5-oxo-1H,4H-1,2,4-triazolo)methylmorpholine; or a pharmaceutically acceptable salt thereof.
Further preferred NK-1 receptor antagonists are those described in PCT International Patent Publication No. WO 95/18124 as compounds of formula (II): 
or a pharmaceutically acceptable salt or prodrug thereof, wherein
R1 is hydrogen, halogen, C1-6alkyl, C1-6alkoxy, CF3, NO2, CN, SRa, SORa, SO2Ra, CO2Ra, CONRaRb, C2-6alkenyl, C2-6alkynyl or C1-4alkyl substituted by C1-4alkoxy, where Ra and Rb each independently represent hydrogen or C1-4alkyl;
R2 is hydrogen, halogen, C1-6alkyl, C1-6alkoxy substituted by C1-4alkoxy or CF3;
R3 is hydrogen, halogen or CF3;
R4 is hydrogen, halogen, C1-6alkyl, C1-6alkoxy, CF3, NO2, CN, SRa, SORa, SO2Ra, CO2Ra, CONRaRb, C2-6alkenyl, C2-6alkynyl or C1-4alkyl substituted by C1-4alkoxy, where Ra and Rb each independently represent hydrogen or C1-4alkyl;
R5 is hydrogen, halogen, C1-6alkyl, C1-6alkoxy substituted by C1-4alkoxy or CF3;
R6 is a 5-membered or 6-membered heterocyclic ring containing 2 or 3 nitrogen atoms optionally substituted by xe2x95x90O, xe2x95x90S or a C1-4alkyl group, and optionally substituted by a group of the formula ZNR7R8 where
Z is C1-6alkylene or C3-6cycloalkylene;
R7 is hydrogen, C1-4alkyl, C3-7cycloalkyl or C3-7cycloalkylC1-4alkyl, or C2-4alkyl substituted by C1-4alkoxy or hydroxyl;
R8 is hydrogen, C1-4alkyl, C3-7cycloalkyl or C3-7cycloalkylC1-4alkyl, or C2-4alkyl substituted by one or two substituents selected from C1-4alkoxy, hydroxyl or a 4, 5 or 6 membered heteroaliphatic ring containing one or two heteroatoms selected from N, O and S;
or R7, R8 and the nitrogen atom to which they are attached form a heteroaliphatic ring of 4 to 7 ring atoms, optionally substituted by a hydroxy group, and optionally containing a double bond, which ring may optionally contain an oxygen or sulphur ring atom, a group S(O) or S(O)2 or a second nitrogen atom which will be part of a NH or NRc moiety where Rc is C1-4alkyl optionally substituted by hydroxy or C1-4alkoxy;
or R7, R8 and the nitrogen atom to which they are attached form a non-aromatic azabicyclic ring system of 6 to 12 ring atoms; or Z, R7 and the nitrogen atom to which they are attached form a heteroaliphatic ring of 4 to 7 ring atoms which may optionally contain an oxygen ring atom;
R9a and R9b are each independently hydrogen or C1-4alkyl, or R9a and R9b are joined so, together with the carbon atoms to which they are attached, there is formed a C5-7 ring;
X is an alkylene chain of 1 to 4 carbon atoms optionally substituted by oxo; and
Y is a C1-4alkyl group optionally substituted by a hydroxyl group; with the proviso that if Y is C1-4alkyl, R6 is substituted at least by a group of formula ZNR7R8 as defined above.
Particularly preferred compounds of formula (II) include:
2-(R)-2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-4-(5-(dimethylamino) methyl-1,2,3-triazol-4-yl)methyl-3-(S)-phenylmorpholine;
(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-4-((dimethylamino-methyl)-1,2,3-triazol-4-yl)methyl)-3-(S)-(4-fluorophenyl)morpholine; or a pharmaceutically acceptable salt thereof.
Further preferred NK-1 receptor antagonists are those described in U.S. Pat. No. 5,691,336 and PCT International Patent Publication No. WO 95/23798 as compounds of formula (III): 
or a pharmaceutically acceptable salt thereof, wherein:
R2 and R3 are independently selected from the group consisting of:
(1) hydrogen,
(2) C1-6 alkyl, unsubstituted or substituted with one or more of the substituents selected from:
(a) hydroxy,
(b) oxo,
(c) C1-6 alkoxy,
(d) phenyl-C1-3 alkoxy,
(e) phenyl,
(f) xe2x80x94CN,
(g) halo,
(h) xe2x80x94NR9R10, wherein R9 and R10 are independently selected from:
(i) hydrogen,
(ii) C1-6 alkyl,
(iii) hydroxy-C1-6 alkyl, and
(iv) phenyl,
(i) xe2x80x94NR9COR10,
(j) xe2x80x94NR9CO2R10,
(k) xe2x80x94CONR9R10,
(l) xe2x80x94COR9, and
(m) xe2x80x94CO2R9;
(3) C2-6 alkenyl, unsubstituted or substituted with one or more of the substituent(s) selected from:
(a) hydroxy,
(b) oxo,
(c) C1-6 alkoxy,
(d) phenyl-C1-3 alkoxy,
(e) phenyl,
(f) xe2x80x94CN,
(g) halo,
(h) xe2x80x94CONR9R10,
(i) xe2x80x94COR9, and
(j) xe2x80x94CO2R9;
(4) C2-6 alkynyl;
(5) phenyl, unsubstituted or substituted with one or more of the substituent(s) selected from:
(a) hydroxy,
(b) C1-6 alkoxy,
(c) C1-6 alkyl,
(d) C2-5 alkenyl,
(e) halo,
(f) xe2x80x94CN,
(g) xe2x80x94NO2,
(h) xe2x80x94CF3,
(i) xe2x80x94(CH2)mxe2x80x94NR9R10,
(j) xe2x80x94NR9COR10,
(k) xe2x80x94NR9CO2R10,
(l) xe2x80x94CONR9R10,
(m) xe2x80x94CO2NR9R10,
(n) xe2x80x94COR9, and
(o) xe2x80x94CO2R9;
and, alternatively, the groups R2 and R3 are joined together to form a carbocyclic ring selected from the group consisting of:
(a) cyclopentyl,
(b) cyclohexyl,
(c) phenyl,
and wherein the carbocyclic ring is unsubstituted or substituted with one or more substituents selected from:
(i) C1-6alkyl,
(ii) C1-6alkoxy,
(iii) xe2x80x94NR9R10,
(iv) halo, and
(v) trifluoromethyl;
and, alternatively, the groups R2 and R3 are joined together to form a heterocyclic ring selected from the group consisting of.
(a) pyrrolidinyl,
(b) piperidinyl,
(c) pyrrolyl,
(d) pyridinyl,
(e) imidazolyl,
(f) furanyl,
(g) oxazolyl,
(h) thienyl, and
(i) thiazolyl,
and wherein the heterocyclic ring is unsubstituted or substituted with one or more substituent(s) selected from:
(i) C1-6alkyl,
(ii) oxo,
(iii) C1-6alkoxy,
(iv) xe2x80x94NR9R10,
(v) halo, and
(vi) trifluoromethyl;
R6, R7 and R8 are independently selected from the group consisting of:
(1) hydrogen;
(2) C1-6 alkyl, unsubstituted or substituted with one or more of the substituents selected from:
(a) hydroxy,
(b) oxo,
(c) C1-6 alkoxy,
(d) phenyl-C1-3 alkoxy,
(e) phenyl,
(f) xe2x80x94CN,
(g) halo,
(h) xe2x80x94NR9R10,
(i) xe2x80x94NR9COR10,
(j) xe2x80x94NR9CO2R10,
(k) xe2x80x94CONR9R10,
(l) xe2x80x94COR9, and
(m) xe2x80x94CO2R9;
(3) C2-6 alkenyl, unsubstituted or substituted with one or more of the substituent(s) selected from:
(a) hydroxy,
(b) oxo,
(c) C1-6 alkoxy,
(d) phenyl-C1-3 alkoxy,
(e) phenyl,
(f) xe2x80x94CN,
(g) halo,
(h) xe2x80x94CONR9R10,
(i) xe2x80x94COR9, and
(j) xe2x80x94CO2R9;
(4) C2-6 alkynyl;
(5) phenyl, unsubstituted or substituted with one or more of the substituent(s) selected from:
(a) hydroxy,
(b) C1-6 alkoxy,
(c) C1-6 alkyl,
(d) C2-5 alkenyl,
(e) halo,
(f) xe2x80x94CN,
(g) xe2x80x94NO2,
(h) xe2x80x94CF3,
(i) xe2x80x94(Ch2)mxe2x80x94NR9R10,
(j) xe2x80x94NR9COR10,
(k) xe2x80x94NR9CO2R10,
(l) xe2x80x94CONR9R10,
(m) xe2x80x94CO2NR9R10,
(n) xe2x80x94COR9, and
(o) xe2x80x94CO2R9;
(6) halo,
(7) xe2x80x94CN,
(8) xe2x80x94CF3,
(9) xe2x80x94NO2,
(10) xe2x80x94SR14, wherein R14 is hydrogen or C1-5alkyl,
(11) xe2x80x94SOR14,
(12) xe2x80x94SO2R14,
(13) NR9COR10,
(14) CONR9COR10,
(15) NR9R10,
(16) NR9CO2R10,
(17) hydroxy,
(18) C1-6alkoxy,
(19) COR9,
(20) CO2R9,
(21) 2-pyridyl,
(22) 3-pyridyl,
(23) 4-pyridyl,
(24) 5-tetrazolyl,
(25) 2-oxazolyl, and
(26) 2-thiazolyl;
R11, R12 and R13 are independently selected from the definitions of R6, R7 and R8, or xe2x80x94OX;
A is selected from the group consisting of:
(1) C1-6 alkyl, unsubstituted or substituted with one or more of the substituents selected from:
(a) hydroxy,
(b) oxo,
(c) C1-6 alkoxy,
(d) phenyl-C1-3 alkoxy,
(e) phenyl,
(f) xe2x80x94CN,
(g) halo,
(h) xe2x80x94NR9R10,
(i) xe2x80x94NR9COR10,
(j) xe2x80x94NR9CO2R10,
(k) xe2x80x94CONR9R10,
(l) xe2x80x94COR9, and
(m) xe2x80x94CO2R9;
(2) C2-6 alkenyl, unsubstituted or substituted with one or more of the substituent(s) selected from:
(a) hydroxy,
(b) oxo,
(c) C1-6 alkoxy,
(d) phenyl-C1-3 alkoxy,
(e) phenyl,
(f) xe2x80x94CN,
(g) halo,
(h) xe2x80x94CONR9R10,
(i) xe2x80x94COR9, and
(j) xe2x80x94CO2R9; and
(3) C2-6 alkynyl;
B is a heterocycle, wherein the heterocycle is selected from the group consisting of: 
and wherein the heterocycle is substituted in addition to xe2x80x94X with one or more substituent(s) selected from:
(i) hydrogen;
(ii) C1-6 alkyl, unsubstituted or substituted with halo, xe2x80x94CF3, xe2x80x94OCH3, or phenyl,
(iii) C1-6 alkoxy,
(iv) oxo,
(v) hydroxy,
(vi) thioxo,
(vii) xe2x80x94SR9,
(viii) halo,
(ix) cyano,
(x) phenyl,
(xi) trifluoromethyl,
(Xii) xe2x80x94(Ch2)mxe2x80x94NR9R10, wherein m is 0, 1 or 2,
(xiii) xe2x80x94NR9COR10,
(xiv) xe2x80x94CONR9R10,
(xv) xe2x80x94CO2R9, and
(xvi) xe2x80x94(Ch2)mxe2x80x94OR9;
p is 0 or 1;
X is selected from:
(a) xe2x80x94PO(OH)Oxe2x88x92.M+, wherein M+ is a pharmaceutically acceptable monovalent counterion,
(b) xe2x80x94PO(Oxe2x88x92)2.2M+,
(c) xe2x80x94PO(Oxe2x88x92)2.D2+, wherein D2+ is a pharmaceutically acceptable divalent counterion,
(d) xe2x80x94CH(R4)xe2x80x94PO(OH)Oxe2x88x92.M+, wherein R4 is hydrogen or C1-3 alkyl,
(e) xe2x80x94CH(R4)xe2x80x94PO(Oxe2x88x92)2.2M+,
(f) xe2x80x94CH(R4)xe2x80x94PO(Oxe2x88x92)2.D2+,
(g) xe2x80x94SO3xe2x80x94.M+,
(h) xe2x80x94CH(R4)xe2x80x94SO3xe2x80x94.M+,
(i) xe2x80x94COxe2x80x94CH2CH2xe2x80x94CO2.M+,
(j) xe2x80x94CH(CH3)xe2x80x94Oxe2x80x94COxe2x80x94R5, wherein R5 is selected from the group consisting of: 
(k) hydrogen, with the proviso that if p is 0 and none of R11, R12 or R13 are xe2x80x94OX, then X is other than hydrogen;
Y is selected from the group consisting of:
(1) a single bond,
(2) xe2x80x94Oxe2x80x94,
(3) xe2x80x94Sxe2x80x94,
(4) xe2x80x94COxe2x80x94,
(5) xe2x80x94CH2xe2x80x94,
(6) xe2x80x94CHR15xe2x80x94, and
(7) xe2x80x94CR15R16xe2x80x94, wherein R15 and R16 are independently selected from the group consisting of:
(a) C1-6 alkyl, unsubstituted or substituted with one or more of the substituents selected from:
(i) hydroxy,
(ii) oxo,
(iii) C1-6 alkoxy,
(iv) phenyl-C1-3 alkoxy,
(v) phenyl,
(vi) xe2x80x94CN,
(vii) halo,
(viii) xe2x80x94NR9R10,
(ix) xe2x80x94NR9COR10,
(x) xe2x80x94NR9CO2R10,
(xi) xe2x80x94CONR9R10,
(xii) xe2x80x94COR9, and
(xiii) xe2x80x94CO2R9;
(b) phenyl, unsubstituted or substituted with one or more of the substituent(s) selected from:
(i) hydroxy,
(ii) C1-6 alkoxy,
(iii) C1-6 alkyl,
(iv) C2-5 alkenyl,
(v) halo,
(vi) xe2x80x94CN,
(vii) xe2x80x94NO2,
(viii) xe2x80x94CF3,
(ix) (Ch2)mxe2x80x94NR9R10,
(x) xe2x80x94NR9COR10,
(xi) xe2x80x94NR9CO2R10,
(xii) xe2x80x94CONR9R10,
(xiii) xe2x80x94CO2NR9R10,
(xiv) xe2x80x94COR9, and
(xv) xe2x80x94CO2R9;
Z is selected from:
(1) hydrogen,
(2) C1-6 alkyl, and
(3) hydroxy, with the proviso that if Y is xe2x80x94Oxe2x80x94, Z is other than hydroxy, or if Y is xe2x80x94CHR15xe2x80x94, then Z and R15 are optionally joined together to form a double bond.
A particularly preferred compound of formula (III) is 2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-3-(S)-(4-fluoro)-phenyl-4-(3-(1-monophosphoryl-5-oxo-1H-1,2,4-triazolo)methyl)morpholine, or a pharmaceutically acceptable salt thereof. In particular, the bis(N-methyl-D-glucamine) salt is preferred.
Further preferred NK-1 receptor antagonists are those described in European Patent Specification No. WO 96/05181, i.e. compounds of formula (IV): 
wherein:
X is a group of the formula NR6R7 or a C- or N-linked imidazolyl ring;
Y is hydrogen or C1-4alkyl optionally substituted by a hydroxy group;
R1 is hydrogen, halogen, C1-6alkyl, C1-6alkoxy, CF3, NO2, CN, SRa, SORa, SO2Ra, CO2Ra, CONRaRb, C2-6alkenyl, C2-6alkynyl or C1-4alkyl substituted by C1-4alkoxy, wherein Ra and Rb each independently represent hydrogen or C1-4alkyl;
R2 is hydrogen, halogen, C1-6alkyl, C1-6alkoxy substituted by C1-4alkoxy or CF3;
R3 is hydrogen, halogen or CF3;
R4 is hydrogen, halogen, C1-6alkyl, C1-6alkoxy, hydroxy, CF3, NO2, CN, SRa, SORa, SO2Ra, CO2Ra, CONRaRb, C2-6alkenyl, C2-6alkynyl or C1-4alkyl substituted by C1-4alkoxy, wherein Ra and Rb are as previously defined;
R5 is hydrogen, halogen, C1-6alkyl, C1-6alkoxy substituted by C1-4alkoxy or CF3;
R6 is hydrogen, C1-6alkyl, C3-7cycloalkyl, C3-7cycloalkylC4alkyl, phenyl, or C2-4alkyl substituted by C1-4alkoxy or hydroxy;
R7 is hydrogen, C1-6alkyl, C3-7cycloalkyl, C3-7cycloalkylC1-4alkyl, phenyl, or C2-4alkyl substituted by one or two substituents selected from C1-4alkoxy, hydroxy or a 4, 5 or 6 membered heteroaliphatic ring containing one or two heteroatoms selected from N, O and S;
or R6 and R7, together with the nitrogen atom to which they are attached, form a saturated or partially saturated heterocyclic ring of 4 to 7 ring atoms, which ring may optionally contain in the ring one oxygen or sulphur atom or a group selected from NRC8S(O) or S(O)2 and which ring may be optionally substituted by one or two groups selected from hydroxyC1-4alkyl, C1-4alkoxyC1-4alkyl, oxo, CORa or CO2Ra where Ra is as previously defined;
or R6 and R7 together with the nitrogen atom to which they are attached, form a non-aromatic azabicyclic ring system of 6 to 12 ring atoms;
R8 is hydrogen, C1-4alkyl, hydroxyC1-4alkyl or C1-4alkoxyC1-4alkyl; and
R9a and R9b are each independently hydrogen or C1-4-alkyl, or R9a and R9b are joined so, together with the carbon atoms to which they are attached, there is formed a C5-7 ring;
and pharmaceutically acceptable salts thereof.
Specific compounds of formula (IV) of use in the present invention include:
2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-3-(S)-(4-fluorophenyl)-4-(4-morpholinobut-2-yn-yl)morpholine;
2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-4-(4-N,N-dimethylaminobut-2-yn-yl)-3-(S)-(4-fluorophenyl)morpholine;
4-(4-azetidinylbut-2-yn-yl)-2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl) ethoxy)-3-(S)-(4-fluorophenyl)morpholine;
2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-3-(S)-(4-fluorophenyl)-4-(4-imidazolylbut-2-yn-yl)morpholine;
2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-3-(S)-(4-fluorophenyl)-4-(4-(N-methylpiperazinyl)but-2-yn-yl)morpholine;
4-(4-bis(2-methoxyethyl)aminobut-2-yn-yl)-2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-3-(S)-(4-fluorophenyl)morpholine;
2-(R)-(1-(R)-(3,6-bis(trifluoromethyl)phenyl)ethoxy)-3-(S)-(4-fluorophenyl)-4-(4-pyrrolidinobut-2-yn-yl)morpholine;
3-(S)-(4-fluorophenyl)-2-(R)-(1-(R)-(3-fluoro-5-(trifluoromethyl)phenyl) ethoxy)-4-(4-morpholinobut-2-yn-yl)morpholine;
3-(S)-(4-fluorophenyl)-4-(4-morpholinobut-2-yn-yl)-2-(R)-(1-(R)-(3-(trifluoromethyl)phenyl)ethoxy)morpholine;
4-(4-azetidinylbut-2-yn-yl)-3-(S)-(4-fluorophenyl)-2-(R)-(1-(R)-(3-(trifluoromethyl)phenyl)ethoxy)morpholine;
2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-4-(4-(N-(2-methoxyethyl)-N-methyl)aminobut-2-yn-yl)-3-(S)-phenylmorpholine;
2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-4-(4-(N-cyclopropyl-N-(2-methoxyethyl)amino)but-2-yn-yl)-3-(S)-phenylmorpholine;
2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-4-(4-(N-isopropyl-N-(2-methoxyethyl)amino)but-2-yn-yl)-3-(S)-phenylmorpholine;
4-(4-(N,N-dimethylamino)but-2-yn-yl)-3-(S)-(4-fluorophenyl)-2-(R)-(1-(S)-(3-fluoro-5-(trifluoromethyl)phenyl-2-hydroxyethoxy)morpholine;
4-(4-azetidinylbut-2yn-yl)-3-(S)-(4-fluorophenyl)-2-(R)-(1-(S)-(3-fluoro-5-(trifluoromethyl)phenyl)-2-hydroxyethoxy)morpholine;
2-(R)-(1-(S)-(3,5-bis(trifluoromethyl)phenyl)-2-hydroxyethoxy)-4-(4-(N,N-dimethylamino)but-2-yn-yl)-3-(S)-(4-fluorophenyl)morpholine;
4-(4-azetidinylbut-2-yn-yl)-2-(R)-(1-(S)-(3,5-bis(trifluoromethyl)phenyl-2-hydroxyethoxy)-3-(S)-(4-fluorophenyl)morpholine;
4-(4-N-bis(2-methoxy)ethyl-N-methylamino)but-2-yn-yl)-2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-3-(S)-(4-fluorophenyl)morpholine;
2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-3-(S)-(4-fluorophenyl)-4-(4-(2-(S)-(methoxymethyl)pyrrolidino)but-2-yn-yl)morpholine;
4-(4-(7-azabicyclo [2.2.1]heptano)but-2-yn-yl)-2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-3-(S)-(4-fluorophenyl)morpholine;
2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-4-(4-diisopropylaminobut-2-yn-yl)-3-(S)-(4-fluorophenyl)morpholine;
2-(R)-(1-(R)-(3-fluoro-5-(trifluoromethyl)phenyl)ethoxy)-4-(4-(2-(S)-(methoxymethyl)pyrrolidino)but-2-yn-yl)-3-(S)-phenylmorpholine;
2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-3-(S)-(4-fluorophenyl)-4-(4-(2-(S)-(hydroxymethyl)pyrrolidino)but-2-yn-yl)morpholine;
and pharmaceutically acceptable salts thereof.
Further preferred NK-1 receptor antagonists are those described in European Patent Publication No. 0 436 334 as compounds of formula (V): 
or a pharmaceutically acceptable salt thereof, wherein
Y is (Ch2)n wherein n is an integer from 1 to 4, and wherein any one of the carbon-carbon single bonds in said (Ch2)n may optionally be replaced by a carbon-carbon double bond, and wherein any one of the carbon atoms of said (Ch2)n may optionally be substituted with R4, and wherein any one of the carbon atoms of said (Ch2)n may optionally be substituted with R7;
Z is (Ch2)m wherein m is an integer from 0 to 6, and wherein any one of the carbon-carbon single bonds of (Ch2)m may optionally be replaced by a carbon-carbon double bond or a carbon-carbon triple bond, and any one of the carbon atoms of said (Ch2)m may optionally be substituted with R8;
R1 is hydrogen or C1-8alkyl optionally substituted with hydroxy, C1-4alkoxy or fluoro;
R2 is a radical selected from hydrogen, C1-6 straight or branched alkyl, C3-7cycloalkyl wherein one of the CH2 groups in said cycloalkyl may optionally be replaced by NH, oxygen or sulphur; aryl selected from phenyl and naphthyl; heteroaryl selected from indanyl, thienyl, furyl, pyridyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, triazolyl, tetrazolyl and quinolyl; phenyl-C2-6alkyl, benzhydryl and benzyl, wherein each of said aryl and heteroaryl groups and the phenyl moieties of said benzyl, phenyl-C2-6alkyl and benzhydryl may optionally be substituted with one or more substituents independently selected from halo, nitro, C1-6alkyl, C1-6alkoxy, trifluoromethyl, amino, C1-6alkylamino, C1-6alkyl-Oxe2x80x94CO, C1-6alkyl-Oxe2x80x94COxe2x80x94C1-6alkyl, C1-6alkyl-COxe2x80x94O, C1-6alkyl-COxe2x80x94C1-6alkyl-Oxe2x80x94, C1-6alkyl-CO, C1-6alkyl-COxe2x80x94C1-6alkyl-, di-C1-6alkylamino, xe2x80x94CONHxe2x80x94C1-6alkyl, C1-6alkyl-COxe2x80x94NHxe2x80x94C1-6alkyl, xe2x80x94NHCOH and xe2x80x94NHCOxe2x80x94C1-6alkyl; and
wherein one of the phenyl moieties of said benzhydryl may optionally be replaced by naphthyl, thienyl, furyl or pyridyl;
R5 is hydrogen, phenyl or C1-6alkyl;
or R2 and R5 together with the carbon to which they are attached, form a saturated ring having from 3 to 7 carbon atoms wherein one of the CH2 groups in said ring may optionally be replaced by oxygen, NH or sulfur;
R3 is aryl selected from phenyl and naphthyl; heteroaryl selected from indanyl, thienyl, furyl, pyridyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, triazolyl, tetrazolyl and quinolyl; and cycloalkyl having 3 to 7 carbon atoms wherein one of the (Ch2) groups in said cycloalkyl may optionally be replaced by NH, oxygen or sulphur;
wherein each of said aryl and heteroaryl groups may optionally be substituted with one or more substituents, and said C3-7cycloalkyl may optionally be substituted with one or two substituents, each of said substituents being independently selected from halo, nitro, C1-6alkyl, C1-6alkoxy, trifluoromethyl, amino, C1-6alkylamino, xe2x80x94COxe2x80x94NHxe2x80x94C1-6alkyl, C1-6alkyl-COxe2x80x94NHxe2x80x94C1-6alkyl, xe2x80x94NHCOH and xe2x80x94NH COxe2x80x94C1-6alkyl;
R4 and R7 are each independently selected from hydroxy, halogen, halo, amino, oxo, cyano, methylene, hydroxymethyl, halomethyl, C1-6alkylamino, di-C1-6alkylamino, C1-6alkoxy, C1-6alkyl-Oxe2x80x94CO, C1-6alkyl-Oxe2x80x94COxe2x80x94C1-6alkyl, C1-6alkyl-COxe2x80x94O, C1-6alkyl-COxe2x80x94C1-6alkyl-Oxe2x80x94, C1-6alkyl-COxe2x80x94, C1-6alkyl-COxe2x80x94C1-6alkyl, and the radicals set forth in the definition of R2;
R6 is xe2x80x94NHCOR9, xe2x80x94NHCH2R9, SO2R8 or one of the radicals set forth in any of the definitions of R2, R4 and R7;
R8 is oximino (xe2x95x90NOH) or one of the radicals set forth in any of the definitions of R2, R4 and R7;
R9 is C1-6alkyl, hydrogen, phenyl or phenylC1-6alkyl;
with the proviso that (a) when m is 0, R8 is absent, (b) when R4, R6, R7 or R8 is as defined in R2, it cannot form together with the carbon to which it is attached, a ring with R5, and (c) when R4 and R7 are attached to the same carbon atom, then either each of R4 and R7 is independently selected from hydrogen, fluoro and C1-6alkyl, or R4 and R7, together with the carbon to which they are attached, for a C3-6 saturated carbocyclic ring that forms a spiro compound with the nitrogen-containing ring to which they are attached.
A particularly preferred compound of formula (V) is (2S,3S)-cis-3-(2-methoxybenzylamino)-2-phenylpiperidine; or a pharmaceutically acceptable salt thereof.
Another class of NK-1 receptor antagonists is as disclosed in PCT International Patent Publication No. WO 93/21155 as compounds of formula (VI): 
or a pharmaceutically acceptable salt thereof, wherein
radicals R are phenyl radicals optionally 2- or 3-substituted by a halogen atom or a methyl radical;
R1 is optionally substituted phenyl, cyclohexadienyl, naphthyl, indenyl or optionally substituted heterocycle;
R2 is H, halogen, OH, alkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, alkyloxy, alkylthio, acyloxy, carboxy, optionally substituted alkyloxycarbonyl, benzyloxycarbonyl, amino or acylamino;
R3 is optionally 2-substituted phenyl;
R4 is OH or fluorine when R5 is H;
or R4 and R5 are OH;
or R4 and R5 together form a bond.
A particularly preferred compound of formula (VI) is (3aS,4S,7aS)-7,7-diphenyl-4-(2-methoxyphenyl)-2-[(2S)-(2-methoxyphenyl)propionyl] perhydroisoindol-4-ol; or a pharmaceutically acceptable salt thereof.
Another class of NK-1 receptor antagonists of use in the present invention is that described in European Patent Publication No. 0 591 040 as compounds of formula (VII): 
wherein
Ar represents an optionally substituted mono-, di- or tricyclic aromatic or heteroaromatic group;
T represents a bond, a hydroxymethylene group, a C1-4alkoxymethylene group or a C1-5alkylene group;
Arxe2x80x2 represents a phenyl group which is unsubstituted or substituted by one or more substituents selected from halogen, preferably chlorine or fluorine, trifluoromethyl, C1-4alkoxy, C1-4alkyl where the said substituents may be the same or different; a thienyl group; a benzothienyl group; a naphthyl group; or an indolyl group;
R represents hydrogen, C1-4alkyl, xe2x80x94C1-4alkoxyC1-4alkyl, or -xe2x80x94C2-4alkanoyloxyC2-14alkyl;
Q represents hydrogen;
or Q and R together form a 1,2-ethylene, 1,3-propylene or 1,4-butylene group;
Am+ represents the radical 
in which X1, X2 and X3, together with the nitrogen atom to which they are attached, form an azabicyclic or azatricyclic ring system optionally substituted by a phenyl or benzyl group; and
Axe2x88x92 represents a pharmaceutically acceptable anion.
A particularly preferred compound of formula (VII) is (+) 1-[2-[3-(3,4-dichlorophenyl)-1-[(3-isopropoxyphenyl)acetyl]-3-piperidinyl]ethyl]-4-phenyl-1-azabicyclo[2,2,2]octane; or a pharmaceutically acceptable salt, especially the chloride, thereof
Another class of NK-1 receptor antagonists of use in the present invention is that described in European Patent Publication No. 0 532 456 as compounds of formula (VIII): 
or a pharmaceutically acceptable salt thereof, wherein
R1 represents an optionally substituted aralkyl, aryloxyalkyl, heteroaralkyl, aroyl, heteroaroyl, cycloalkylcarbonyl, aralka noyl, heteroarylalkanoyl, aralkoxycarbonyl or arylcarbamoyl group or the acyl group of an (-amino acid optionally N-substituted by a lower alkanoyl or carbamoyl-lower alkanoyl group;
R2 represents cycloalkyl or an optionally substituted aryl or heteroaryl group;
R3 represents hydrogen, alkyl, carbamoyl or an alkanoyl or alkenoyl group optionally substituted by carboxy or esterified or amidated carboxy;
R4 represents an optionally substituted aryl group or an optionally partially saturated heteroaryl group;
X1 represents methylene, ethylene, a bond, an optionally ketalised carbonyl group or an optionally etherified hydroxymethylene group;
X2 represents alkylene, carbonyl or a bond; and
X3 represents carbonyl, oxo-lower alkyl, oxo(aza)-lower alkyl, or an alkyl group optionally substituted by phenyl, hydroxymethyl, optionally esterified or amidated carboxy, or (in other than the (-position) hydroxy.
A particularly preferred compound of formula (VIII) is (2R*,4S*)-2-benzyl-1-(3,5-dimethylbenzoyl)-N-(4-quinolinylmethyl)-4-piperidineamine; or a pharmaceutically acceptable salt thereof.
Another class of NK-1 receptor antagonists of use in the present invention is that described in European Patent Publication No. 0 443 132 as compounds of formula (IX): 
or a pharmaceutically acceptable salt thereof, wherein
wherein R1 is aryl, or a group of the formula: 
or a pharmaceutically acceptable salt thereof, wherein
X is CH or N; and
Z is O or Nxe2x80x94R5, in which R5 is hydrogen or lower alkyl;
R2 is hydroxy or lower alkoxy;
R3 is hydrogen or optionally substituted lower alkyl;
R4 is optionally substituted ar(lower)alkyl;
A is carbonyl or sulfonyl; and
Y is a bond or lower alkenylene.
A particularly preferred compound of formula (IX) is the compound of formula (IXa) 
Another class of NK-1 receptor antagonists of use in the present invention is that described in PCT International Patent Publication No. WO 92/17449 as compounds of the formula (X): 
or a pharmaceutically acceptable salt thereof, wherein
R1 is aryl selected from indanyl, phenyl and naphthyl; heteroaryl selected from thienyl, furyl, pyridyl and quinolyl; and cycloalkyl having 3 to 7 carbon atoms, wherein one of said carbon atoms may optionally be replaced by nitrogen, oxygen or sulfur; wherein each of said aryl and heteroaryl groups may optionally be substituted with one or more substituents, and said C3-7cycloalkyl may optionally be substituted with one or two substituents, said substituents being independently selected from chloro, fluoro, bromo, iodo, nitro, C1-10alkyl optionally substituted with from one to three fluoro groups, C1-10alkoxy optionally substituted with from one to three fluoro groups, amino, C1-10alkyl-Sxe2x80x94, C1-10alkyl-S(O)xe2x80x94, C1-10alkylxe2x80x94SO2xe2x80x94, phenyl, phenoxy, C1-10alkylxe2x80x94SO2NHxe2x80x94, C1-10alkylxe2x80x94SO2NHxe2x80x94C1-10alkyl-, C1-10alkylamino-diC1-10alkyl-, cyano, hydroxy, cycloalkoxy having 3 to 7 carbon atoms, C1-6alkylamino, C1-6dialkylamino, HC(O)NHxe2x80x94 and C1-10alkyl-C(O)NHxe2x80x94; and
R2 is thienyl, benzhydryl, naphthyl or phenyl optionally substituted with from one to three substituents independently selected from chloro, bromo, fluoro, iodo, cycloalkoxy having 3 to 7 carbon atoms, C1-10alkyl optionally substituted with from one to three fluoro groups and C1-10alkoxy optionally substituted with from one to three fluoro groups.
A particularly preferred compound of formula (X) is (2S,3S)-3-(2-methoxy-5-trifluoromethoxybenzyl)-amino-2-phenylpiperidine; or a pharmaceutically acceptable salt thereof.
Another class of NK-1 receptor antagonists of use in the present invention is that described in PCT International Patent Publication No. WO 95/08549 as compounds of formula (XI): 
wherein R1 is a C1-4alkoxy group;
R2 is 
R3 is a hydrogen or halogen atom;
R4 and R5 may each independently represent a hydrogen or halogen atom, or a C1-4 alkyl, C1-4 alkoxy or trifluoromethyl group;
R6 is a hydrogen atom, a C1-4 alkyl, (Ch2)m cyclopropyl, xe2x80x94S(O)nC1-4 alkyl, phenyl, NR7R8, CH2C(O)CF3 or trifluoromethyl group;
R7 and R8 may each independently represent a hydrogen atom, or a C1-4 alkyl or acyl group;
x represents zero or 1;
n represents zero, 1 or 2;
m represents zero or 1;
and pharmaceutically acceptable salts and solvates thereof.
A particularly preferred compound of formula (XI) is [2-methoxy-5-(5-trifluoromethyl-tetrazol-1-yl)-benzyl]-(2S-phenyl-piperidin-3S-yl)-amine; or a pharmaceutically acceptable salt thereof.
Another class of NK-1 receptor antagonists of use in the present invention is that described in PCT International Patent Publication No. WO 97/49710 as compounds of formula (XII): 
wherein R1, R2, R3, R4, R5, R6, R9, R10, and X are as defined therein.
Particularly preferred compounds of formula (XII) are
(3S,5R,6S)-3-[2-cyclopropoxy-5-(trifluoromethoxy)phenyl]-6-phenyl-1-oxa-7-aza-spiro [4.5]decane;
(3R,5R,6S)-3-[2-cyclopropoxy-5-(trifluoromethoxy)phenyl]-6-phenyl-1-oxa-7-aza-spiro[4.5]decane; or a pharmaceutically acceptable salt thereof.
Another class of tachykinin receptor antagonists of use in the present invention is that described in PCT International Patent Publication No. WO 95/06645 as compounds of formula (XIII): 
wherein
R represents a hydrogen atom or a C1-4 alkoxy group;
R1 is selected from phenyl, optionally substituted by a group xe2x80x94(CH2)nCONR3R4 or S(O)mR3; or a 5- or 6-membered aromatic heterocycle containing 1, 2, 3 or 4 heteroatoms selected from oxygen, nitrogen, or sulphur, optionally substituted by a C1-4 alkyl, trifluoromethyl or cyano group or a group xe2x80x94(CH2)nCONR3R4;
R2 represents a hydrogen or halogen atom;
R3 and R4 independently represent hydrogen or C1-4 alkyl;
n represents zero, 1 or 2;
m represents zero 1 or 2;
z represents zero or 1;
and pharmaceutically acceptable salts and solvates thereof.
A particularly preferred compound of formula (XII) is [5-(5-methyl-tetrazol-1-yl)-benzofuran-7-ylmethyl]-(2S-phenyl-piperidin-3S-yl)-amine; or a pharmaceutically acceptable salt thereof.
Another class of tachykinin receptor antagonists of use in the present invention is that described in PCT International Patent Publication No. WO 95/14017, i.e. compounds of formula (XIV) 
or a pharmaceutically acceptable salt thereof, wherein
m is zero, 1, 2 or 3;
n is zero or 1;
o is zero, 1 or 2;
p is zero or 1;
R is phenyl, 2- or 3-indolyl, 2- or 3-indolinyl, benzothienyl, benzofuiranyl, or naphthyl;
which R groups may be substituted with one or two halo, C1-3alkoxy, trifluoromethyl, C1-4alkyl, phenyl-C1-3alkoxy, or C1-4alkanoyl groups;
R1 is trityl, phenyl, diphenylmethyl, phenoxy, phenylthio, piperazinyl, piperidinyl, pyrrolidinyl, morpholinyl, indolinyl, indolyl, benzothienyl, hexamethyleneiminyl, benzofuranyl, tetrahydropyridinyl, quinolinyl, isoquinolinyl, reduced quinolinyl, reduced isoquinolinyl, phenyl-(C1-4alkyl)-, phenyl-(C1-4alkoxy)-, quinolinyl-(C1-4alkyl)-, isoquinolinyl-(C1-4alkyl)-, reduced quinolinyl-(C1-4alkyl)-, reduced isoquinolinyl-(C1-4alkyl)-, benzoyl-(C1-3alkyl)-, C1-4alkyl, or xe2x80x94NHxe2x80x94CH2xe2x80x94R5;
any one of which R1 groups may be substituted with halo, C1-4alkyl, C1-4alkoxy, trifluoromethyl, amino, C1-4alkylamino, di(C1-4alkyl)amino, or C2-4alkanoylamino;
or any one of which R1 groups may be substituted with phenyl, piperazinyl, C3-8cycloalkyl, benzyl, C1-4alkyl, piperidinyl, pyridinyl, pyrimidinyl, C2-6alkanoylamino, pyrrolidinyl, C2-6alkanoyl, or C1-4alkoxycarbonyl;
any one of which groups may be substituted with halo, C1-4alkyl, C1-4alkoxy, trifluoromethyl, amino, C1-4alkylamino, di(C1-4alkyl)amino, or C2-4alkanoylamino;
or R1 is amino, a leaving group, hydrogen, C1-4alkylamino, or di(C1-4alkyl)amino;
R5 is pyridyl, anilio-(C1-3-alkyl)-, or anilinocarbonyl;
R2 is hydrogen, C1-4alkyl, C1-4alkylsulfonyl, carboxy-(C1-3alkyl)-, C1-3alkoxycarbonyl-(C1-3alkyl)-, or xe2x80x94COxe2x80x94R6;
R6 is hydrogen, C1-4alkyl, C1-3haloalkyl, phenyl, C1-3alkoxy, C1-3hydroxyalkyl, amino, C1-4alkylamino, di(C1-4alkyl)amino, or xe2x80x94(CH2)qxe2x80x94R7;
q is zero to 3;
R7 is carboxy, C1-4alkoxycarbonyl, C1-4alkylcarbonyloxy, amino, C1-4alkylamino, di(C1-4alkyl)amino, C1-6alkoxycarbonylamino, orphenoxy, phenylthio, piperazinyl, piperidinyl, pyrrolidinyl, morpholinyl, indolinyl, indolyl, benzothienyl, benzofuranyl, quinolinyl, phenyl-(C1-4alkyl)-, quinolinyl-(C1-4alkyl)-, isoquinolinyl-(C1-4alkyl)-, reduced quinolinyl-(C1-4alkyl)-, reduced isoquinolinyl-(C1-4alkyl)-, benzoyl-C1-3alkyl;
any one of which aryl or heterocyclic R7 groups may be substituted with halo, trifluoromethyl, C1-4alkoxy, C1-4alkyl, amino, C1-4alkylamino, di(C1-4alkyl)amino, or C2-4alkanoylamino;
or any one of which R7 groups may be substituted with phenyl, piperazinyl, C3-8cycloalkyl, benzyl, piperidinyl, pyridinyl, pyrimidinyl, pyrrolidinyl, C2-6alkanoyl, or C1-4alkoxycarbonyl;
any of which groups may be substituted with halo, trifluoromethyl, amino, C1-4alkoxy, C1-4alkyl, C1-4alkylamino, di(C1-4alkyl)amino, or C2-4alkanoylamino;
R8 is hydrogen or C1-6alkyl;
R3 is phenyl, phenyl-(C1-6alkyl)-, C3-8-cycloalkyl, C5-8cycloalkenyl, C1-8alkyl, naphthyl, C2-8alkenyl, or hydrogen;
any one or which groups except hydrogen may be substituted with one or two halo, C1-3alkoxy, C1-3alkylthio, nitro, trifluoromethyl, or C1-3alkyl groups; and
R4 is hydrogen or C1-3alkyl;
with the proviso that if R1 is hydrogen or halo, R3 is phenyl, phenyl-(C1-6alkyl)-, C3-8cycloalkyl, C5-8cycloalkenyl, or naphthyl.
A particularly preferred compound of formula (XIII) is [N-(2-methoxybenzyl)acetylamino]-3-(1H-indol-3-yl)-2-[N-(2-(4-piperidin-1-yl)piperidin-1-yl)acetylamino]propane; or a pharmaceutically acceptable salt thereof.
The preferred compounds of formulae (I), (II), (III) and (IV) will have the 2- and 3-substituents on the morpholine ring in the cis arrangement, the preferred stereochemistry being as shown in the following general formula: 
Where the benzyloxy moiety is xcex1-substituted, the preferred stereochemistry of the xcex1-carbon is either (R) when the substituent is an alkyl (e.g. methyl) group or (S) when the substituent is a hydroxyalkyl (e.g. hydroxymethyl) group.
The preparation of the foregoing compounds is fully described in the referenced patents and publications.
Unless otherwise defined herein, suitable alkyl groups include straight-chained and branched alkyl groups containing from 1 to 6 carbon atoms. Typical examples include methyl and ethyl groups, and straight-chained or branched propyl and butyl groups. Particular alkyl groups are methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl and tert-butyl.
Unless otherwise defined herein, suitable alkenyl groups include straight-chained and branched alkenyl groups containing from 2 to 6 carbon atoms. Typical examples include vinyl and allyl groups.
Unless otherwise defined herein, suitable alkynyl groups include straight-chained and branched alkynyl groups containing from 2 to 6 carbon atoms. Typical examples include ethynyl and propargyl groups.
Unless otherwise defined herein, suitable cycloalkyl groups include groups containing from 3 to 7 carbon atoms. Particular cycloalkyl groups are cyclopropyl and cyclohexyl.
Unless otherwise defined herein, suitable aryl groups include phenyl and naphthyl groups. A particular aryl-C1-6alkyl, e.g. phenyl-C1-6alkyl, group is benzyl.
Unless otherwise defined herein, suitable heteroaryl groups include pyridyl, quinolyl, isoquinolyl, pyridazinyl, pyrimidinyl, pyrazinyl, pyranyl, furyl, benzofuryl, thienyl, benzthienyl, imidazolyl, oxadiazolyl and thiadiazolyl groups.
The term xe2x80x9chalogenxe2x80x9d as used herein includes fluorine, chlorine, bromine and iodine. The compounds of use in this invention may have one or more asymmetric centres and can therefore exist as enantiomers and possibly as diastereoisomers. It is to be understood that the present invention relates to the use of all such isomers and mixtures thereof.
Suitable pharmaceutically acceptable salts of the NK-1 receptor antagonists of use in the present invention include acid addition salts which may, for example, be formed by mixing a solution of the compound with a solution of a pharmaceutically acceptable non-toxic acid such as hydrochloric acid, fumaric acid, maleic acid, succinic acid, acetic acid, citric acid, tartaric acid, carbonic acid, phosphoric acid or sulphuric acid. Salts of amine groups may also comprise the quaternary ammonium salts in which the amino nitrogen atom carries an alkyl, alkenyl, alkynyl or aralkyl group. Where the compound carries an acidic group, for example a carboxylic acid group, the present invention also contemplates salts thereof, preferably non-toxic pharmaceutically acceptable salts thereof, such as the sodium, potassium and calcium salts thereof.
The above compounds are only illustrative of the neurokinin-1 (NK-1) antagonists which are currently under investigation. As this listing of compounds is not meant to be comprehensive, the methods of the present invention may employ any neurokinin-1 receptor antagonist, in particular a neurokinin-1 receptor antagonist which is orally active, long acting and CNS-penetrant. Accordingly, the present invention is not strictly limited to any particular structural class of compound.
Certain of the above defined terms may occur more than once in the above formula and upon such occurrence each term shall be defined independently of the other. Similarly, the use of a particular variable within a noted structural formula is intended to be independent of the use of such variable within a different structural formula.
Full descriptions of the preparation of the tachykinin receptor antagonists which are employed in the present invention may be found in the references cited herein.
The present invention accordingly provides the use of a NK-1 receptor antagonist selected from the compounds of formulae (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), (XI), (XII), (XIII) and (XIV) for the manufacture of a medicament for treating or preventing a psychosomatic disorder or a psychoimmunologic disorder or ameliorating the symptoms attendant to a psychosomatic disorder or a psychoimmunologic disorder in a patient.
The present invention also provides a method for treating or preventing a psychosomatic disorder or a psychoimmunologic disorder or ameliorating the symptoms attendant to a psychosomatic disorder or a psychoimmunologic disorder in a patient, which method comprises administration to a patient in need of such treatment an effective amount of a NK-1 receptor antagonist selected from the compounds of formulae (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), (XI), (XII), (XIII) and (XIV).
In a further aspect of the present invention, there is provided a pharmaceutical composition for treating or preventing a psychosomatic disorder or a psychoimmunologic disorder or ameliorating the symptoms attendant to a psychosomatic disorder or a psychoimmunologic disorder in a patient comprising a NK-1 receptor antagonist selected from the compounds of formulae (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), (XI), (XII), (XIII) and (XIV), together with at least one pharmaceutically acceptable carrier or excipient.
The identification of a compound as a tachykinin receptor antagonist, in particular, a neurokinin-1 receptor antagonist, and thus able to have utility in the present invention may be readily determined without undue experimentation by methodology well known in the art.
It is well recognized in the art that psychological stimuli can precipitate or alter the course of numerous diseases or disorders. As used herein a xe2x80x9cpsychosomatic disorderxe2x80x9d is a disease or disorder for which the physical etiology is contributed to directly or indirectly by psychological factors. As used herein a xe2x80x9cpsychoimmunologic disorderxe2x80x9d is an immunologic disease or disorder wherein an immunological response is influenced directly or indirectly by psychological factors.
Accordingly, the present invention provides methods for the treatment or prevention of a psychosomatic disorder or a psychoimmunologic disorder wherein the physical etiology or immunological response is contributed to directly or indirectly by psychological factors in the origin or progression of diseases and disorders such as alopecia areata, angina pectoris nervosa, asthma, atopoic dermatitis, autonomic imbalance, bacterial infections, bronchial asthma, cancer, cerebrovascular disease, collage vascular diseases, diabetes mellitus, duodenal ulcer, dyspnoeneurosis, essential hypertension, gastric ulcer, hypersensitive skin response, hypertension, inflammatory skin disorders, leukemia, malignancy, multiple sclerosis, myocardial infarction, neurodermatitis, neurotic emesis, peptic ulcer, psoriasis, puritis, respiratory illness, rheumatoid arthritis, systemic lupus erythematosus, thyrotoxicosis, ulcreative colitis, varicella zoster, and viral infection. As will be readily appreciated by one skilled in the art, psychological pressures which contribute to the clinical course of such psychosomatic or psychoimmunologic diseases and disorders may be only a contributing factor to the penultimate state of the disorder or disease. In addition, the psychological pressures which contribute to the clinical course of such psychosomatic or psychoimmunologic diseases and disorders interact with numerous other factors, including the patient""s hereditary predisposition, personality features, and the autonomic and endocrine effects that arise in response to individual vicissitudes.
A tachykinin receptor antagonist may be administered alone or in combination by oral, parenteral (e.g., intramuscular, intraperitoneal, intravenous or subcutaneous injection, or implant), nasal, vaginal, rectal, sublingual, or topical routes of administration and can be formulated in dosage forms appropriate for each route of administration.
Preferably the compositions according to the present invention are in unit dosage forms such as tablets, pills, capsules, powders, granules, solutions or suspensions, or suppositories, for oral, parenteral or rectal administration, by inhalation or insufflation or administration by trans-dermal patches or by buccal cavity absorption wafers.
For preparing solid compositions such as tablets, the principal active ingredient is mixed with a pharmaceutical carrier, e.g. conventional tableting ingredients such as corn starch, lactose, sucrose, sorbitol, talc, stearic acid, magnesium stearate, dicalcium phosphate or gums, and other pharmaceutical diluents, e.g. water, to form a solid preformulation composition containing a homogeneous mixture of a compound of the present invention, or a non-toxic pharmaceutically acceptable salt thereof. When referring to these preformulation compositions as homogeneous, it is meant that the active ingredient is dispersed evenly throughout the composition so that the composition may be readily subdivided into equally effective unit dosage forms such as tablets, pills and capsules. This solid preformulation composition is then subdivided into unit dosage forms of the type described above containing from 0.1 to about 500 mg of the active ingredient of the present invention. The tablets or pills of the novel composition can be coated or otherwise compounded to provide a dosage form affording the advantage of prolonged action. For example, the tablet or pill can comprise an inner dosage and an outer dosage component, the latter being in the form of an envelope over the former. The two components can be separated by an enteric layer which serves to resist disintegration in the stomach and permits the inner component to pass intact into the duodenum or to be delayed in release. A variety of materials can be used for such enteric layers or coatings, such materials including a number of polymeric acids and mixtures of polymeric acids with such materials as shellac, cetyl alcohol and cellulose acetate.
The liquid forms in which the novel compositions of the present invention may be incorporated for administration orally or by injection include aqueous solutions, suitably flavoured syrups, aqueous or oil suspensions, and flavoured emulsions with edible oils such as cottonseed oil, sesame oil, coconut oil, peanut oil or soybean oil, as well as elixirs and similar pharmaceutical vehicles. Suitable dispersing or suspending agents for aqueous suspensions include synthetic and natural gums such as tragacanth, acacia, alginate, dextran, sodium carboxymethylcellulose, methylcellulose, polyvinyl-pyrrolidone or gelatin.
Preferred compositions for administration by injection include those comprising a NK-1 receptor antagonist as the active ingredient, in association with a surface-active agent (or wetting agent or surfactant) or in the form of an emulsion (as a water-in-oil or oil-in-water emulsion).
Suitable surface-active agents include, in particular, non-ionic agents, such as polyoxyethylenesorbitans (e.g. Tween(trademark) 20, 40, 60, 80 or 85) and other sorbitans (e.g. Span(trademark) 20, 40, 60, 80 or 85). Compositions with a surface-active agent will conveniently comprise between 0.05 and 5% surface-active agent, and preferably between 0.1 and 2.5%. It will be appreciated that other ingredients may be added, for example mannitol or other pharmaceutically acceptable vehicles, if necessary.
Suitable emulsions may be prepared using commercially available fat emulsions, such as Intralipid(trademark), Liposyn(trademark), Infonutrol(trademark), Lipofundin(trademark) and Lipiphysan(trademark). The active ingredient may be either dissolved in a pre-mixed emulsion composition or alternatively it may be dissolved in an oil (e.g. soybean oil, safflower oil, cottonseed oil, sesame oil, corn oil or almond oil) and an emulsion formed upon mixing with a phospholipid (e.g. egg phospholipids, soybean phospholipids or soybean lecithin) and water. It will be appreciated that other ingredients may be added, for example glycerol or glucose, to adjust the tonicity of the emulsion. Suitable emulsions will typically contain up to 20% oil, for example, between 5 and 20%. The fat emulsion will preferably comprise fat droplets between 0.1 and 1.0 xcexcm, particularly 0.1 and 0.5 xcexcm, and have a pH in the range of 5.5 to 8.0.
Compositions for inhalation or insufflation include solutions and suspensions in pharmaceutically acceptable, aqueous or organic solvents, or mixtures thereof, and powders. The liquid or solid compositions may contain suitable pharmaceutically acceptable excipients as set out above. Preferably the compositions are administered by the oral or nasal respiratory route for local or systemic effect. Compositions in preferably sterile pharmaceutically acceptable solvents may be nebulised by use of inert gases. Nebulised solutions may be breathed directly from the nebulising device or the nebulising device may be attached to a face mask, tent or intermittent positive pressure breathing machine. Solution, suspension or powder compositions may be administered, preferably orally or nasally, from devices which deliver the formulation in an appropriate manner.
Compositions of the present invention may also be presented for administration in the form of trans-dermal patches using conventional technology. The compositions may also be administered via the buccal cavity using, for example, absorption wafers.
Compositions in the form of tablets, pills, capsules or wafers for oral administration are particularly preferred.
It will be known to those skilled in the art that there are numerous compounds which may be used for treating or preventing a psychosomatic disorder or a psychoimmunologic disorder in a patient. Combinations of these therapeutic agents some of which have also been mentioned herein with a tachykinin receptor antagonist will bring additional, complementary, and often synergistic properties to enhance the desirable properties of these various therapeutic agents. In these combinations, the tachykinin receptor antagonist and the therapeutic agents may be independently present in dose ranges from one one-hundredth to one times the dose levels which are effective when these compounds are used singly. In such combination therapy, the tachykinin receptor antagonist may be administered with the other therapeutic agent (e.g., concurrently, concombinantly, sequentially, or in a unitary formulation) such that their therapeutic efficacy overlap.
The tachykinin receptor antagonist may be administered in combination with stimulants, hypnotics, anxiolytics, antipsychotics, antianxiety agents, minor tranquilizers, benzodiazepines, barbituates, serotonin agonists, selective serotonin reuptake inhibitors, 5HT-2 antagonists, non-steroidal anti-inflammatory drugs, oral contraceptives, progesterone, progestin, monoamine oxidase inhibitors, and the like, or the tachykinin receptor antagonist may be administered in conjunction with the use of physical methods such as electrical stimulation.
For example, for treating or preventing a psychosomatic disorder or a psychoimmunologic disorder in a patient a tachykinin receptor antagonist may be given in combination with such compounds as: adinazolam, allobarbital, alonimid, alprazolam, amitriptyline, amobarbital, amoxapine, bentazepam, benzoctamine, brotizolam, bupropion, busprione, butabarbital, butalbital, caffeine, capuride, carbocloral, chloral betaine, chloral hydrate, chlordiazepoxide, clomipramine, cloperidone, clorazepate, clorethate, clozapine, cyprazepam, deanol, desipramine, dexclamol, dextroamphetamine, diazepam, dichloralphenazone, divalproex, diphenhydramine, doxepin, estazolam, ethchlorvynol, etomidate, fenobam, flunitrazepam, flurazepam, fluvoxamine, fluoxetine, fosazepam, glutethimide, halazepam, hydroxyzine, imipramine, lithium, lorazepam, lormetazepam, maprotiline, mecloqualone, melatonin, mephobarbital, meprobamate, methaqualone, methylphenidate, midaflur, midazolam, nefazodone, nisobamate, nitrazepam, nortriptyline, oxazepam, paraldehyde, paroxetine, pemoline, pentobarbital, perlapine, perphenazine, phenelzine, phenobarbital, prazepam, promethazine, propofol, protriptyline, quazepam, reclazepam, roletamide, secobarbital, sertraline, suproclone, temazepam, thioridazine, tracazolate, tranylcypromaine, trazodone, triazolam, trepipam, tricetamide, triclofos, trifluoperazine, trimetozine, trimipramine, uldazepam, valproate, venlafaxine, zaleplon, zolazepam, zolpidem, and salts thereof, and combinations thereof, and the like, as well as admixtures and combinations thereof.
Typically, the individual daily dosages for these combinations may range from about one-fifth of the minimally recommended clinical dosages to the maximum recommended levels for the entities when they are given singly. In the case of methylphenidate the recommended clinical dose is generally from approximately 5 mg/day to approximately 20 mg/day, however, the dosage may be titrated, beginning at low doses and increasing to optimal levels (decrease in symptoms, improvement in task performance, and no side effects).
To illustrate these combinations, a tachykinin receptor antagonist effective clinically at a given daily dose range may be effectively combined, at levels which are equal or less than the daily dose range, with the aforementioned compounds. It will be readily apparent to one skilled in the art that the tachykinin receptor antagonist may be employed with other agents for treating or preventing a psychosomatic disorder or a psychoimmunologic disorder or ameliorating the symptoms attendant to a psychosomatic disorder or a psychoimmunologic disorder in a patient.
Naturally, these dose ranges may be adjusted on a unit basis as necessary to permit divided daily dosage and, as noted above, the dose will vary depending on the nature and severity of the disease, weight of patient, special diets and other factors. These combinations may be formulated into pharmaceutical compositions as known in the art and as discussed herein.
The dosage of active ingredient in the compositions of this invention may be varied, however, it is necessary that the amount of the active ingredient be such that a suitable dosage form is obtained. The active ingredient may be administered to patients (animals and human) in need of such treatment in dosages that will provide optimal pharmaceutical efficacy. The selected dosage depends upon the desired therapeutic effect, on the route of administration, and on the duration of the treatment. The dose will vary from patient to patient depending upon the nature and severity of disease or disorder, the patient""s weight, special diets then being followed by a patient, concurrent medication, the intrinsic tachykinin receptor antagonist activity of the compound, the bioavailability upon oral administration of the compound and other factors which those skilled in the art will recognize.
In the treatment of a condition in accordance with the present invention, an appropriate dosage level will generally be about 0.01 xcexcg to 50 mg per kg patient body weight per day which may be administered in single or multiple doses. Preferably, the dosage level will be about 0.1 xcexcg to about 25 mg/kg per day; more preferably about 0.5 xcexcg to about 10 mg/kg per day. For example, for treating or preventing a psychosomatic disorder or a psychoimmunologic disorder or ameliorating the symptoms attendant to a psychosomatic disorder or a psychoimmunologic disorder in a patient, a suitable dosage level is about 0.1 xcexcg to 25 mg/kg per day, preferably about 0.5 xcexcg to 10 mg/kg per day, and especially about 1 xcexcg to 5 mg/kg per day. In larger mammals, for example humans, a typical indicated dose is about 300 xcexcg to 400 mg orally. A compound may be administered on a regimen of several times per day, for example 1 to 4 times per day, preferably once or twice per day. When using an injectable formulation, a suitable dosage level is about 0.1 xcexcg to 10 mg/kg per day, preferably about 0.5 xcexcg to 5 mg/kg per day, and especially about 1 xcexcg to 1 mg/kg per day. In larger mammals, for example humans, a typical indicated dose is about 100 xcexcg to 100 mg i.v. A compound may be administered on a regimen of several times per day, for example 1 to 4 times per day, preferably once or twice per day, and more preferably once a day.
Pharmaceutical compositions of the present invention may be provided in a solid dosage formulation preferably comprising about 100 xcexcg to 500 mg active ingredient, more preferably comprising about 100 xcexcg to 250 mg active ingredient. The pharmaceutical composition is preferably provided in a solid dosage formulation comprising about 100 xcexcg, 1 mg, 5 mg, 10 mg, 25 mg, 50 mg, 100 mg, 200 mg or 300 mg active ingredient. A minimum dosage level for the NK-1 receptor antagonist is generally about 5 mg per day, preferably about 10 mg per day and especially about 20 mg per day. A maximum dosage level for the NK-1 receptor antagonist is generally about 1500 mg per day, preferably about 1000 mg per day and especially about 500 mg per day.
It will be appreciated that the amount of the NK-1 receptor antagonist required for use in treating or preventing a psychosomatic disorder or a psychoimmunologic disorder or ameliorating the symptoms attendant to a psychosomatic disorder or a psychoimmunologic disorder in a patient will vary not only with the particular compounds or compositions selected but also with the route of administration, the nature of the condition being treated, and the age and condition of the patient, and will ultimately be at the discretion of the patient""s physician or pharmacist. The length of time during which a tachykinin receptor antagonist will be given varies on an individual basis.
The compounds of formulae (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), (XI), (XII), (XIII) and (XIV) may be prepared by the methods described in EP-A-0 577 394 (or WO 95/16679), WO 95/18124, WO 95/23798, WO 96/05181, EP-A-0 436 334, WO 93/21155, EP-A-0 591 040, EP-A-0 532 456, EP-A-0 443 132, WO 92/17449, WO 95/08549, WO 97/49710, WO 95/06645 and WO 95/14017, respectively.
Particularly preferred NK-1 receptor antagonists of the formulae (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), (XI), (XII), (XIII) and (XIV) for use in the present invention are compounds which are potent NK-1 receptor antagonists, i.e. compounds with an NK-1 receptor affinity (IC50) of less than 10 nM.
A particularly preferred class of NK-1 receptor antagonist of use in the present invention are those compounds which are orally active, long acting and CNS-penetrant. Such compounds may be identified using the pharmacological assays described hereinafter. The use of this sub-class of NK-1 antagonists for treating or preventing a psychosomatic disorder or a psychoimmunologic disorder or ameliorating the symptoms attendant to a psychosomatic disorder or a psychoimmunologic disorder in a patient represents a further aspect of the present invention.
Thus, the present invention provides the use of a CNS penetrant NK-1 receptor antagonist in an oral, once-a-day medicament for treating or preventing a psychosomatic disorder or a psychoimmunologic disorder or ameliorating the symptoms attendant to a psychosomatic disorder or a psychoimmunologic disorder in a patient. The compounds of this class advantageously exhibit a rapid onset of action and a reduced side-effect profile when compared against conventional methods for treating or preventing a psychosomatic disorder or a psychoimmunologic disorder in a patient.
In particular, the present invention provides a means for the identification of NK-1 receptor antagonists which would be especially effective in an oral once-a-day medicament for treating or preventing a psychosomatic disorder or a psychoimmunologic disorder or ameliorating the symptoms attendant to a psychosomatic disorder or a psychoimmunologic disorder in a patient.
The exceptional pharmacology of the class of NK-1 receptor antagonists of use in the present invention enables treating or preventing a psychosomatic disorder or a psychoimmunologic disorder or ameliorating the symptoms attendant to a psychosomatic disorder or a psychoimmunologic disorder in a patient, without the need for concomitant therapy and in particular, without the need for concomitant use of a serotonin agonist or an SSRI.
Furthermore, the exceptional pharmacology of the class of NK-1 receptor antagonists of use in the present invention results in a rapid onset of action.
The present invention accordingly provides the use of an orally active, long acting, CNS-penetrant NK-1 receptor antagonist (as hereinafter defined) for the manufacture of a medicament adapted for oral administration for treating or preventing a psychosomatic disorder or a psychoimmunologic disorder or ameliorating the symptoms attendant to a psychosomatic disorder or a psychoimmunologic disorder in a patient.
The present invention also provides a method for treating or preventing a psychosomatic disorder or a psychoimmunologic disorder or ameliorating the symptoms attendant to a psychosomatic disorder or a psychoimmunologic disorder in a patient, which method comprises the oral administration to a patient in need of such treatment of an effective amount of an orally active, long acting, CNS-penetrant NK-1 receptor antagonist (as defined herein).
In a further aspect of the present invention, there is provided an oral pharmaceutical composition for treating or preventing a psychosomatic disorder or a psychoimmunologic disorder or ameliorating the symptoms attendant to a psychosomatic disorder or a psychoimmunologic disorder in a patient which comprises an orally active, long acting, CNS-penetrant NK-1 receptor antagonist (as hereinafter defined), together with a pharmaceutically acceptable carrier or excipient.
It will be appreciated to those skilled in the art that reference herein to treatment extends to prophylaxis (prevention) as well as the treatment of the noted diseases/disorders and symptoms. Because the specific diagnosis of a psychosomatic disorder or a psychoimmunologic disorder in a particular patient may be difficult, the patient may benefit from the prophylactic administration of a subject compound in accordance with the present invention.
Preferred NK-1 receptor antagonists for use in the present invention as orally active, long acting, CNS-penetrant NK-1 receptor antagonists are selected from the classes of compounds described in European Patent Specification No. 0 577 394, and International Patent Specification Nos. 95/08549, 95/18124, 95/23798, 96/05181 and WO 97/49710.
Particularly preferred NK-1 receptor antagonists of use in the present invention include:
(xc2x1)-(2R3R,2S3S)-N-{[2-cyclopropoxy-5-(trifluoromethoxy)phenyl]methyl}-2-phenylpiperidin-3amine;
2-(S)-(3,5-bis(trifluoromethyl)benzyloxy)-3(S)-(4-fluorophenyl)-4-(3-(5-oxo-1H,4H-1,2,4-triazolo)methyl)morpholine;
2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-4-(3-(5-oxo-1H,4H-1,2,4-triazolo)methyl)-3-(S)-phenyl-morpholine;
2-(S)-(3,5-bis(trifluoromethyl)benzyloxy)-4-(3-(5-oxo-1H,4H-1,2,4-triazolo)methyl)-3-(S)-phenyl-morpholine;
2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-3-(S)-(4-fluorophenyl)-4-(3-(5-oxo-1H,4H-1,2,4-triazolo)methyl)morpholine;
2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-4-(5-(N,N-dimethylamino)methyl-1,2,3-triazol-4-yl)methyl-3-(S)-phenylmorpholine;
2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-4-(5-(N,N-dimethylamino)methyl-1,2,3-triazol-4-yl)methyl-3-(S)-(4-fluorophenyl)morpholine;
(3S,5R,6S)-3-[2-cyclopropoxy-5-(trifluoromethoxy)phenyl]-6-phenyl-1-oxa-7-aza-spiro[4.5]decane;
(3R,5R,6S)-3-[2-cyclopropoxy-5-(trifluoromethoxy)phenyl]-6-phenyl-1-oxa-7-aza-spiro[4.5]decane;
2-(R)-(1-(S)-(3,5-bis(trifluoromethyl)phenyl)-2-hydroxyethoxy)-3-(S)-(4-fluorophenyl)-4-(1,2,4-triazol-3-yl)methylmorpholine;
2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-3-(S)-(4-fluorophenyl)-4-(3-(4-monophosphoryl-5-oxo-1H-1,2,4-triazolo)methyl)morpholine;
2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-3-(S)-(4-fluorophenyl)-4-(3-(1-monophosphoryl-5-oxo-1H-1,2,4-triazolo)methyl)morpholine;
2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-3-(S)-(4-fluorophenyl)-4-(3-(2-monophosphoryl-5-oxo-1H-1,2,4-triazolo)methyl)morpholine;
2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-3-(S)-(4-fluorophenyl)-4-(3-(5-oxyphosphoryl-1H-1,2,4-triazolo)methyl)morpholine;
2-(S)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-3-(S)-(4-fluorophenyl)-4-(3-(1-monophosphoryl-5-oxo-4H-1,2,4-triazolo)methyl)morpholine;
2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-4-(4-N,N-dimethylaminobut-2-yn-yl)-3-(S)-(4-fluorophenyl)morpholine; or a pharmaceutically acceptable salt thereof.
Full descriptions of the preparation of the tachykinin receptor antagonists which may be employed in the present invention may be found in the references cited herein.
The following examples are provided for the purpose of further illustration only and are not intended to be limitations on the disclosed invention.